Obesity is a multi-faceted chronic condition and is the most prevalent nutritional problem in the United States today. Obesity, a condition caused by an excess of energy intake as compared to energy expenditure, contributes to the pathogenesis of hypertension, type II or non-insulin dependent diabetes mellitus, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, heart disease, pancreatitis, and such common forms of cancer such as breast cancer, prostate cancer, uterine cancer and colon cancer.
At present, only a limited number of drugs for treating obesity are commercially available. Unfortunately, while some of these drugs may bring short-term relief to the patient, a long-term successful treatment has not yet been achieved. Exemplary methods of treating obesity are also disclosed in U.S. Pat. Nos. 3,867,539; 4,446,138; 4,588,724; 4,745,122; 5,019,594; 5,300,298; 5,403,851; 5,567,714; 5,573,774; 5,578,613; and 5,900,411.
One of the presently available drugs for treating obesity, developed by Hoffman-LaRoche, is an inhibitor of pancreatic lipase (PL). Pancreatic lipase is responsible for the degradation of triglycerides to monoglycerides. However, it has been associated with side-effects such as severe diarrhea resulting in absorption inhibition of only one specific fraction of fatty acids and, has been known to induce allergic reactions. Treatment with PL inhibitors is thus highly disadvantageous and may even expose the treated subject to life-threatening risks.
Recently, it has been suggested that fat absorption may be reduced by inhibiting the activity of the microsomal triglyceride-transfer protein (MTP), which is involved in the formation and secretion of very light density lipoproteins (VLDL) and chylomicrons. Sharp et al., [Nature (1993) 365:65-69] and Wetterau et al., [Science (1994) 282:751-754,] demonstrated that the mtp gene is responsible for abetalipoproteinemia disease. U.S. Pat. Nos. 6,066,650, 6,121,283 and 6,369,075 describe compositions that include MTP inhibitors, which are aimed at treating various conditions associated with excessive fat absorption. However, patients treated with MTP inhibitors suffer major side effects including hepatic steatosis, which are attributed to reduced MTP activity in both intestine and liver. This is not surprising since people naturally deficient for MTP activity were shown to develop fatty livers [Kane and Havel (1989); Disorders of the biogenesis and secretion of lipoproteins containing the apolipoprotein B. pp. 1139-1164 in: “The metabolic basis of inherited disease” (Scrivers et al., eds.). McGraw-Hill, New York]. In fact, the company Brystol Myers Squibb, that developed MTP inhibitors for the treatment of obesity, has recently decided to abandon this target, due to this fatty liver side effect.
The presently known targets for the treatment of obesity and related disorders can be divided into four main classes: (i) appetite blockers, which include for example the NPY (neuropeptide Y); (ii) satiety stimulators, which include, for example, the product of the ob, db and agouti genes; (iii) energy or fatty acid burning agents, which include the UCPs (Uncoupling Proteins); and (iv) fat absorption inhibitors such as those acting on PL and MTP in the intestine, described above.
As discussed herein, the use of these targets is highly limited by their redundancy, their multiple targeting and/or their lack of tissue specificity.
There is thus a widely recognized need for, and it would be highly advantageous to have compositions and methods for treating obesity and related diseases and disorders devoid of the above limitations.
Serine proteases are involved in a large number of important physiological processes. Selective inhibition of a given serine protease is one of the strategies for the treatment of pathological conditions associated with the activity or overactivity of these serine proteases. Below is a non-exhaustive list of serine protease inhibitors disclosed in the literature:                phosphorus-based inhibitors such as the diisopropylphosphofuloridate (DFP) (Jansen et al., (1952) Adv. Enzymol. 13: 321-343) or diphenyl phosphonate ester analogues;        fluorine-containing serine proteases, such as trifluoromethyl ketones (TFMKs);        peptide-based aldehydes, chloromethyl ketones, fluoromethyl ketones, dimethyl sulphonium salts, α-keto-acids and amides, α-keto esters and α-keto-aldehydes (glyoxals);        natural products such as the cyclotheonamides, derived from the Japanese marine sponge Theonella sp.;        molecules based on heterocyclic structure;        N-hydroxysuccimide heteorcycles and related compounds;        isocoumarins such as 3,4-dichloroisocoumarin;        β lactam-based inhibitors;        metal-potentiated compounds;        aprotinin (Trasylol®), used to reduce bleeding; and        serpins (serine protease inhibitors) such as antithrombin and α-1-antitrypsin having a role in coagulation/thrombosis and emphysema/A1AT respectively.        
However, few compounds have been described as serine protease inhibitors with a specific and selective inhibition of a unique target. Moreover, no compounds have been disclosed or suggested, to selectively and specifically inhibit the enteropeptidase, and to be used in the treatment of obesity, excess weight or diseases associated with an abnormal fat metabolism.
Enteropeptidase is a serine protease situated on the surface of epithelial intestinal cells (enterocytes) (Lancet. 1969 Apr. 19; 1(7599):812-3; Am J Physiol Gastrointest Liver Physiol. 2003 December; 285(6):G1235-41; Proc Soc Exp Biol Med. 1994 June; 206(2):114-8; Ciba Found Symp. 1979 Jan. 16-18; (70):169-87; Lancet. 1982 Aug. 28; 2(8296):504). The substrate of enteropeptidase is trypsinogen, a precursor to trypsin. Enteropeptidase converts trypsinogen into a molecule of trypsin. In turn, trypsin, which is also a serine protease, converts the precursors of a series of digestive enzymes, such as procarboxypeptidases A and B, chymotrypsinogen, pancreatic prolipase and pro-elastase, into the active forms of the enzymes (carboxypeptidases A and B, chymotrypsin, pancreatic lipase and elastase). The latter active forms of such digestive enzymes are required for the processing and ultimate absorption of protein and fat matter in the gastrointestinal (GI) tract.
Because enteropeptidase is located in the intestinal lumen, inhibition of this enzyme requires that the compounds selectively inhibit enteropeptidase without interfering with circulating serine proteases, such as thrombin, kalikrein, and the like.
Thus, there is a need for compounds to treat obesity, excess overweight as well as diseases associated with an abnormal fat metabolism, on a long term basis that have a specific target.
It is an object of the present invention to provide compounds that inhibit enteropeptidase, and more particular that selectively inhibit enteropeptidase. In particular, these compounds are non-absorbable i.e., they do not pass from the intestine into the blood.
It is another object of the present invention to provide compounds that are derivatives of boroanalogs of amino acids incorporating a protonatable functionality on their side chain, such as borolysine, boroornithine, boroarginine and the like, and are strong, non-absorbable inhibitors of enteropeptidase.
Yet another object of the invention, are compositions, especially pharmaceutical compositions, comprising at least one of the compounds disclosed in the present invention.
It is also another object of the invention to provide methods to treat obesity, excess weight or diseases associated with an abnormal fat metabolism, comprising administrating, to a mammal in need thereof, at least one of the compounds disclosed in the present invention or a composition described in the present invention.
Yet another object of the present invention is the use of at least one of the compounds or of the composition disclosed herein, for the treatment of obesity, excess weight and diseases associated with an abnormal fat metabolism. A compound or a composition of the invention for use in the treatment of obesity, excess weight and diseases associated with an abnormal fat metabolism, is also provided.
These and other objects are achieved by the present invention as evidence by the summary of the invention, description of the preferred embodiments and the claims.